Abstract 5571: Genome-wide crosstalk of estrogen and progesterone signaling in breast cancer

Abstract

Abstract Estrogen receptor alpha (ER) and progesterone receptor (PR) are established biomarkers in breast cancer and receptor-targeted therapies are routinely used in breast cancer treatment. Estrogen receptor exists as two subtypes, ERα and ERβ, and PR has two isoforms PRA and PRB. Furthermore, millions of women worldwide use estrogen and progesterone formulations as oral contraceptives and hormone replacement therapies. Although critical crosstalk occurs between estrogen and progesterone signaling, the global nature and mechanistic details of this interaction are not known. Our central hypothesis is that there is genome-wide dominance of progesterone over estrogen signaling in breast cancer. This hypothesis is based on our novel findings that gene expression and proliferation of T47D and ZR75 breast cancer cells upon co-treatment with estrogen and progesterone is similar to progesterone-only treatment and is significantly different from estrogen-only treatment. Furthermore, four derivative T47D sublines that lack either of the PR isoforms, both the isoforms of PR or ER along with PR are being used to study ERα-, PRA- and PRB-specific regulatory networks. ER- and PR-regulated gene networks are defined by correlating ER and PR genome binding data obtained from ChIP-seq with gene expression data of T47D cells acquired using RNA-seq. For instance, genes that are known to be important in breast carcinogenesis, such as GATA3, GREB1, PDZK1, FOXA1 are found to be co-regulated by ER and PR. Subsequently the intersection of identified ER- and PR-regulated gene networks will be studied and their clinical value will be assessed. Transcription cofactors FOXA1 and NF1C are critical for transactivation by ER and PR. Knockdown of these cofactors in T47D cells alters the ER/PR crosstalk in these cells. To validate the clinical value of genes co-regulated by ER and PR in breast cancer, meta-analysis for their enrichment in established breast cancer signatures will be done. Cluster analysis of the expression of these genes in patient tumor samples that differ in clinical outcomes will also be performed. Finally, a Kaplan-Meier survival analysis will be done to study a correlation between expression of these genes and patient survival. These innovative studies will determine the global influence of progesterone over estrogen signaling in breast cancer. The resulting map of ER- and PR-regulated gene networks will lead to the optimization of breast cancer treatments, hormonal contraceptives and hormone replacement therapies. Citation Format: Hari Singhal, Geoffrey Greene. Genome-wide crosstalk of estrogen and progesterone signaling in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5571. doi:10.1158/1538-7445.AM2014-5571